2-OXO-1,2,3,4-TETRAHYDROQUINOLINE DERIVATIVES

Abstract: The invention concerns a 2-oxo-1,2,3,4-tetrahydroquinoline derivative of formula (I) wherein Q is 2-oxo-1,2,3,4-tetrahydroquinolin-6-yl which bears on the nitrogen atom at the 1-position a (1-4C)alkyl substituent; X<1> is thio, sulphinyl or sulphonyl; Ar is optionally-substituted 1,3-phenylene; R<1> is (1-4C)alkyl, (3-4C)alkenyl or (3-4C)alkynyl; and R<2> and R<3> together form a group of the formula -A<2>-X<2>-A<3>- which together with the carbon atom to which A<2> and A<3> are attached define a ring having 5 or 6 ring atoms, wherein each of A<2> and A<3> is (1-3C)alkylene and X<2> is oxy; or a pharmaceutically-acceptable salt thereof; processes for their preparation; pharmaceutical compositions containing them and their use as 5-lipoxygenase inhibitors.

Description: 2-0X0-1,2,3, -TETRAHYDROQϋINOLINE DERIVATIVES This invention concerns 2-oxo-l,2,3,4-tetrahydroquinoline derivatives and more particularly 2-oxo-l,2,3,4-tetrahydroquinoline derivatives which are inhibitors of the enzyme 5-lipoxygenase (hereinafter referred to as 5- O). The invention also concerns processes for the manufacture of said 2-oxo-1,2,3, -tetrahydro- quinoline derivatives and novel pharmaceutical compositions containing them. Also included in the invention is the use of said 2-oxo-l,2,3,4-tetrahydroquinoline derivatives in the treatment of various diseases such as inflammatory and/or allergic diseases in which the direct or indirect products of 5- O catalysed oxidation of arachidonic acid are involved, and the production of new medicaments for such use. As stated above the 2-oxo-l,2,3,4-tetrahydroquinoline derivatives described hereinafter are inhibitors of 5-LO, which enzyme is known to be involved in catalysing the oxidation of arachidonic acid to give rise via a cascade process to the physiologically active leukotrienes such as leukotriene B, (LTB,) and the peptido-lipid leukotrienes such as leukotriene C, ( TC,) and leukotriene D, (LTD.) and various metabolites. The biosynthetic relationship and physiological properties of the leukotrienes are summarised by G.W. Taylor and S.R. Clarke in Trends in Pharmacological Sciences, 1986, _, 100-103. The leukotrienes and their metabolites have been implicated in the production and development of various diseases, for example various inflammatory and allergic diseases such as inflammation of the joints (especially rheumatoid arthritis, osteoarthritis and gout), inflammation of the gastrointestinal tract (especially inflammatory bowel disease, ulcerative colitis and gastritis), skin diseases (especially psoriasis, eczema and dermatitis), ocular conditions (especially allergic conjunctivitis and uveitis) and respiratory disease (especially asthma, bronchitis and allergic rhinitis), for example in the production and development of various cardiovascular and cerebrovascular disorders such as myocardial infarction, the formation of atherosclerotic plaques, hypertension, platelet aggregation, angina, stroke, reperfusion injury, vascular injury including restenosis and peripheral vascular disease, for example in the formation of the conditions of shock or trauma such as can follow burn injuries, toxaemia or surgery, and for example various disorders of bone metabolism such as osteoporosis (including senile and postmenopausal osteoporosis), Paget's disease, bone metastases, hypercalcaemia, hyperparathyroidism, osteosclerosis, osteopetrosis and periodontitis, and the abnormal changes in bone metabolism which may accompany rheumatoid arthritis and osteoarthritis. In addition the leukotrienes are mediators of inflammatory diseases by virtue of their ability to modulate lymphocyte and leukocyte function. Other physiologically active metabolites of arachidonic acid, such as the prostaglandins and thromboxanes, arise via the' action of the enzyme cyclooxygenase on arachidonic acid. It is disclosed in European Patent Application No. 0385662 that certain heterocyclic derivatives possess inhibitory properties against 5-L0. In particular European Patent Application No. 0420511 is also concerned with heterocyclic derivatives which possess inhibitory properties against 5-LO. We have now discovered that certain 2-oxo-l,2,3,4-tetrahydroquinoline derivatives which lie within the scope of disclosure of European Patent Application No. 0420511 but which were not specifically disclosed within that document are preferred inhibitors of the enzyme 5-LO and thus of leukotriene biosyntheses. Thus such compounds are of value as therapeutic agents in the treatment of, for example, allergic conditions, psoriasis, asthma, cardiovascular and cerebrovascular disorders, and/or inflammatory and arthritic conditions, and/or disorders of bone metabolism, mediated alone or in part by one or more leukotrienes. It has been found that certain compounds disclosed in European Patent Application No. 0420511 are non-crystalline, for example they are formed in an oily or gummy state or they are isolated as foams. Such non-crystalline compounds are undesirable when consideration is given toward the preparation, purification, analysis, handling and formulation of larger quantities of the compounds. Thus the compound 4-[3-(1,2-dihydro-l-ethyl-2-oxoquinolin-6-ylthio)phenyl]- 4-methoxytetrahydropyran (Example 2 of EPA 0420511) was obtained as a gum and the compound (2RS,4SR)-4-[3-(l,2-dihydro-l-methyl-2- oxoquinolin-6-ylthio)-5-fluorophenyl]-4-methoxy-2-methyltetrahydro- pyran (Example 5 of EPA 0420511) was obtained as an oil. According to the present invention there is provided a 2-oxo-l,2,3,4-tetrahydroquinolinyl derivative of the formula I OR 1 I Q-X 1 -Ar-C-R 2 I I R 3 wherein Q is 2-oxo-l,2,3,4-tetrahydroquinolin- ' 6-yl which bears on the nitrogen atom at the 1-position a (l-4C)alkyl substituent; X is thio, sulphinyl or sulphonyl; Ar is 1,3-phenylene which may optionally bear one or two halogeno substituents; R 1 is (l-4C)alkyl, (3-4C)alkenyl or (3-4C)alkynyl; and 2 3 2 2 3 R and R together form a group of the formula -A -X -A - which 2 3 together with the carbon atom to which A and A are attached define a 2 3 ring having 5 or 6 ring atoms, wherein A and A , which may be the 2 same or different, each is (l-3C)alkylene and X is oxy, and which ring may bear one or two (l-4C)alkyl substituents; or a pharmaceutically-acceptable salt thereof. In this specification the generic term "alkyl" includes both straight-chain and branched-chain alkyl groups. However references to individual alkyl groups such as "propyl" are specific for the straight-chain version only and references to individual branched-chain alkyl groups such as "isopropyl" are specific for the branched-chain version only. An analogous convention applies to other generic terms. It is further to be understood that, insofar as certain of the compounds of formula I defined above may exist in optically active or racemic forms by virtue of one or more asymmetric carbon atoms, the invention includes in its definition any such optically active or racemic form which possesses the property of inhibiting 5-LO. The synthesis of optically active forms may be carried out by standard techniques of organic chemistry well known in the art, for example by synthesis from optically active starting materials or by resolution of a racemic form. Suitable values for the generic terms referred to above include those set out below. A suitable value for the (1-4C)alkyl substituent which is present on Q is, for example, methyl, ethyl or propyl. A suitable value for a halogeno substituent which may be present on Ar is, for example, fluoro. A suitable value for R when it is (l-4C)alkyl is, for example, methyl, ethyl or propyl; when it is (3-4C)alkenyl is, for example, allyl; and when it is (3-4C)alkynyl is, for example, 2-propynyl. 2 3 When R and R together form a group of the formula 2 2 3 2 3 -A -X -A - which together with the carbon atom to which A and A are attached define a ring having 5 or 6 ring atoms then a suitable value 2 3 for A or A , which may be the same or different, when each is (l-3C)alkylene is, for example, methylene, ethylene or trimethylene. Suitable values for the (1-4C)alkyl substituents which may be present on said 5- or 6-membered ring include, for example, methyl and ethyl. A suitable pharmaceutically-acceptable salt of a compound of the invention is, for example, an acid-addition salt of a compound of the invention which is sufficiently basic, for example, an acid-addition salt with, for example, an inorganic or organic acid, for example hydrochloric, hydrobromic, sulphuric, phosphoric, trifluoroacetic, citric or maleic acid. In addition a suitable pharmaceutically-acceptable salt of a compound of the invention which is sufficiently acidic is an alkali metal salt, for example a sodium or potassium salt, an alkaline earth metal salt, for example a calcium or magnesium salt, an ammonium salt or a salt with an organic base which affords a physiologically-acceptable cation, for example a salt with methylamine, dimethylamine, trimethylamine, piperidine, morpholine or tris-(2-hydroxyethyl)amine. Particular compounds of the invention include, for example, 2-oxo-l,2,3,4-tetrahydroquinoline derivatives of the formula I, or pharmaceutically-acceptable salts thereof, wherein the variable groups Q, X 1, Ar, R1, R2 and R3 have the values disclosed hereinbefore or hereinafter in this section concerning particular compounds of the invention:- (a) Q is l-methyl-2-oxo-l,2,3,4-tetrahydroquinolin-6-yl; (b) X is thio or sulphonyl; (c) Ar is 1,3-phenylene or 5-fluoro-l,3-phenylene; (d) Ar is 2,5-difluoro-l,3-phenylene; (e) R is methyl; or 2 3 2 2 3 (f) R and R together form a group of the formula -A -X -A - 2 3 which together with the carbon atom to which A and A are attached 2 define a ring having 5 or 6 ring atoms, wherein A is methylene or 3 2 ethylene, A is ethylene and X is oxy, and which ring may bear a 2 methyl substituent alpha to X . A preferred compound of the invention comprises a 2-oxo-l,2,3,4-tetrahydroquinoline derivative of the formula I wherein Q is l-methyl-2-oxo-l,2,3,4-tetrahydroquinolin-6-yl; X is thio or sulphonyl; Ar is 1,3-phenylene or 5-fluoro-l,3-phenylene; R is methyl; and 2 3 2 2 3 R and R together form a group of the formula -A -X -A - which 2 3 together with the carbon atom to which A and A are attached define a 2 3 2 ring having 6 ring atoms, wherein each of A and A is ethylene and X 2 is oxy, and which ring may bear a methyl substituent alpha to X ; or a pharmaceutically-acceptable salt thereof. A further preferred compound of the invention comprises a 2-oxo-l,2,3,4-tetrahydroquinoline derivative of the formula I wherein Q is l-methyl-2-oxo-l,2,3,4-tetrahydroquinolin-6-yl; X is thio or sulphonyl; Ar is 1,3-phenylene, 5-fluoro-l,3-phenylene or 2,5-difluoro-1,3-phenylene; R is methyl; and 2 3 2 2 3 R and R together form a group of the formula -A -X -A - which 2 3 together with the carbon atom to which A and A are attached define a 2 3 2 ring having 6 ring atoms, wherein each of A and A is ethylene and X 2 is oxy, and which ring may bear a methyl substituent alpha to X ; or a pharmaceutically-acceptable salt thereof. A further preferred compound of the invention comprises a 2-oxo-l,2,3,4-tetrahydroquinoline derivative of the formula I wherein Q is l-methyl-2-oxo-l,2,3,4-tetrahydroquinolin-6-yl; X is thio or sulphonyl; Ar is 5-fluoro-l,3-phenylene; R is methyl; and ? 3 R and R together form a group of the formula -CH 2 CH 2 OCH(CH 3 )CH 2 -; or a pharmaceutically-acceptable salt thereof. A further preferred compound of the invention comprises a 2-oxo-l,2,3,4-tetrahydroquinoline derivative of the formula I wherein Q is l-methyl-2-oxo-l,2,3,4-tetrahydroquinolin-6-yl; X is thio or sulphonyl; Ar is 5-fluoro-l,3-phenylene or 2,5-difluoro-l,3-phenylene; R is methyl; and 2 3 R and R together form a group of the formula -CH 2 CH 2 0CH(CH-.)CH 2 -; or a pharmaceutically-acceptable salt thereof. A specific preferred compound of the invention is the following compound of the formula I:- (2S, R)-4-[5-fluoro-3-(l-methyl-2-oxo-l,2,3, -tetrahydroquinolin-6- ylthio)phenyl]-4-methoxy-2-methyltetrahydropyran. A specific especially preferred compound of the invention is the following compound of the formula I:- (2S,4R)-4-[5-fluoro-3-(l-methyl-2-oxo-1,2,3,4-tetrahydroquinolin-6- ylsulphonyl)phenyl)-4-methoxy-2-methyltetrahydropyran. A specific especially preferred compound of the invention is the following compound of the formula I:- (2S, R)-4-[2,5-difluoro-3-(l-methyl-2-oxo-1,2,3,4-tetrahydroquinolin- 6-ylthio)phenyl]-4-methoxy-2-methyltetrahydropyran. In a further aspect of the invention we have discovered that certain compounds of the invention are crystalline. This has, for example, been established for compounds such as those disclosed within Examples 1 to 9 hereinafter. Thus such compounds are of value when their preparation on a larger scale is required as the purification, analysis and handling of a material is facilitated if it is formed in the crystalline state. It is known, for example, that the removal of solvent residues from non-crystalline, oily materials is problematical. In addition the preparation of a pharmaceutical composition comprising a crystalline material is a conventional procedure. The composition may, for example, be in a form suitable for oral use such as a tablet or capsule; or, for example, in a form suitable for administration by inhalation, for example as a finely divided powder or a microcrystalline form. Such options for the formulation of the material are precluded should it be formed in an oily state. A compound of the invention comprising a 2-oxo-l,2,3,4-tetrahydroquinoline derivative of the formula I, or a pharmaceutically-acceptable salt thereof, may be prepared by any process known to be applicable to the preparation of structurally-related compounds. Such procedures are provided as a further feature of the invention and are illustrated by the following representative examples in which, unless otherwise stated, Q, X , Ar, 1 2 3 R , R and R have any of the meanings defined hereinbefore. (a) The coupling, conveniently in the presence of a suitable bbaassee,, ooff aa compound of the formula Q-X -H with a compound of the formula II OR Z-Ar-C-R II R" wherein Z is a displaceable group. A suitable displaceable group Z is, for example, a halogeno or sulphonyloxy group, for example a fluoro, chloro, bromo, iodo, methane- sulphonyloxy or toluene-4-sulphonyloxy group. A suitable base for the coupling reaction is, for example, an alkali or alkaline earth metal carbonate, (l-4C)alkoxide, hydroxide or hydride, for example sodium carbonate, potassium carbonate, sodium ethoxide, potassium butoxide, lithium hydroxide, sodium hydroxide, potassium hydroxide, sodium hydride or potassium hydride, or an organometallic base such as (l-4C)alkyl-lithium, for example n-butyl-lithium. The coupling reaction is conveniently performed in a suitable inert solvent or diluent, for example N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidin-2-one, dimethylsulphoxide, acetone, 1,2-dimethoxyethane or tetrahydrofuran, and at a temperature in the range, for example, 10 to 150°C, conveniently at or near 100°C. Conveniently the reaction may be performed in the presence of a suitable catalyst, for example a metallic catalyst, for example palladium(O) or copper(I) such as tetrakis(triphenylphosphine)- palladiu , cuprous chloride or cuprous bromide. The starting materials of the formula Q-X -H and of the formula II may be obtained by standard procedures of organic chemistry. The preparation of such starting materials is described within the accompanying non-limiting Examples. Alternatively necessary starting materials are obtainable by analogous procedures to those illustrated which are within the ordinary skill of an organic chemist. The disclosure of European Patent Application No. 0420511 is particularly relevant to the preparation of suitable starting materials. (b) The coupling, conveniently in the presence of a suitable base as defined hereinbefore, of a compound of the formula Q-Z, wherein Z is a displaceable group as defined hereinbefore, with a compound of the formula III OR 1 I H-X^Ar-C-R 2 III I R 3 The coupling reaction is conveniently performed in a suitable inert solvent as defined hereinbefore and at a temperature in the range, for example, 10 to 150°C, conveniently at or near 100°C. The reaction may conveniently be performed in the presence of a suitable catalyst as defined hereinbefore. The starting materials of the formula Q-Z and of the formula III may be obtained by standard procedures of organic chemistry. The preparation of such starting materials is described within the accompanying non-limiting Examples. Alternatively necessary starting materials are obtainable by analogous procedures to those illustrated which are within the ordinary skill of an organic chemist. The disclosure of European Patent Application No. 0420511 is particularly relevant to the preparation of suitable starting materials. (c) The coupling of a compound of the formula Q-X -Z, wherein Z is a displaceable group as defined hereinbefore or, when X is a thio group, Z may be a group of the formula Q-X -, with an organometallic reagent of the formula IV OR 1 I M-Ar-C-R 2 IV I R 3 wherein H is an alkali metal or alkaline earth metal such as lithium or calcium or H represents the magnesium halide portion of a conventional Grignard reagent. The coupling reaction is conveniently performed in a suitable inert solvent or diluent as defined hereinbefore and at a temperature in the range, for example, -80 to +50°C, conveniently in the range -80°C to ambient temperature. The preparation of the starting materials of the formula • Q-X -Z and of the formula IV may be obtained by standard procedures of organic chemistry. Alternatively necessary starting materials are obtainable by analogous procedures to those illustrated which are within the ordinary skill of an organic chemist. The disclosure of the European Patent Application set out hereinbefore is particularly relevant to the preparation of suitable starting materials. (d) The alkylation, conveniently in the presence of a suitable base as defined hereinbefore, of a compound of the formula V OH I Q-X 1 -Ar-C-R 2 V I R 3 with a compound of the formula R -Z, wherein Z is a displaceable group as defined hereinbefore. The alkylation reaction is conveniently performed in a suitable inert solvent or diluent as defined hereinbefore and at a temperature in the range, for example, -20 to +70°C, conveniently at or near ambient temperature. The preparation of the starting materials of the formula V may be obtained by standard procedures of organic chemistry. Alternatively necessary starting materials are obtainable by analogous procedures to those illustrated in the European Patent Application set out hereinbefore. (e) For the production of those compounds of the formula I wherein Q bears an alkyl substituent on an available nitrogen atom, the alkylation of a compound of the formula I wherein Q bears a hydrogen atom on said available nitrogen atom. A suitable alkylating agent is, for example, any agent known in the art for the alkylation of an available nitrogen atom, for example an alkyl halide, for example a (1-4C)alkyl chloride, bromide or iodide, in the presence of a suitable base as defined hereinbefore. The alkylation reaction is preferably performed in a suitable inert solvent or diluent, for example N,N-dimethylformamide, N,N-dimethylacetamide, dimethylsulphoxide, acetone, 1,2-dimethoxyethane or tetrahydrofuran, and at a temperature in the range, for example, 10 to 150°C, conveniently at or near ambient temperature. (f) For the production of those compounds of the formula I wherein X is a sulphinyl or sulphonyl group, the oxidation of a compound of the formula I wherein X is a thio group. A suitable oxidising agent is, for example, any agent known in the art for the oxidation of thio to sulphinyl and/or sulphonyl, for example, hydrogen peroxide, a peracid (such as 3- chloroperoxybenzoic or peroxyacetic acid), an alkali metal peroxysulphate (such as potassium peroxy onosulphate) , chromium trioxide or gaseous oxygen in the presence of platinum. The oxidation is generally carried out under as mild conditions as possible and with the required stoichiometric amount of oxidising agent in order to reduce the risk of over oxidation and damage to other functional groups. In general the reaction is carried out in a suitable solvent or diluent such as methylene chloride, chloroform, acetone, tetrahydrofuran or tert-butyl methyl ether and at a temperature, for example, at or near ambient temperature, that is in the range 15 to 35°C. When a compound carrying a sulphinyl group is required a milder oxidising agent may also be used, for example ' sodium or potassium metaperiodate, conveniently in a polar solvent such as acetic acid or ethanol. It will be appreciated that when a compound of the formula I containing a sulphonyl group is required, it may be obtained by oxidation of the corresponding sulphinyl compound as well as of the corresponding thio compound. When a pharmaceutically-acceptable salt of a novel compound of the formula I is required, it may be obtained, for example, by reaction of said compound with a suitable acid or base using a conventional procedure. When an optically active form of a compound of the formula I is required, it may be obtained by carrying out one of the aforesaid procedures using an optically active starting material, or by resolution of a racemic form of said compound using a conventional procedure. As stated previously, the compounds of the formula I are inhibitors of the enzyme 5-L0. The effects of this inhibition may be demonstrated using one or more of the standard procedures set out below:- a) An ij vitro assay system involving incubating a test compound with heparinised human blood, prior to challenge with the calcium ionophore A23187 and then indirectly measuring the inhibitory effects on 5-L0 by assaying the amount of LTB, using specific radioimmunoassays described by Carey and Forder (F. Carey and R.A. Forder, Prostaglandins, Leukotrienes Med. , 1986, 22_, 57; Prostaglandins, 1984, 28, 666; Brit. J. Pharmacol. 1985, 84, 34P) which involve the use of a protein-LTB, conjugate produced using the procedure of Young et alia (Prostaglandins, 1983, 26(4), 605-613). The effects of a test compound on the enzyme cyclooxygenase (which is involved in the alternative metabolic pathway for arachidonic acid and gives rise to prostaglandins, thro boxanes and related metabolites) may be measured at the same time using the specific radioimmunoassay for thromboxane B„(TxB 2 ) described by Carey and Forder (see above). This test provides an indication of the effects of a test compound against 5-L0 and also cyclooxygenase in the presence of blood cells and proteins. It permits the selectivity of the inhibitory effect on 5-L0 or cyclooxygenase to be assessed. b) An ex vivo assay system, which is a variation of test a) above, involving administration to a group of rats of a test compound (usually orally as the suspension produced when a solution of the test compound in dimethylsulphoxide is added to carboxymethylcellulose) , blood collection, heparinisation, challenge with A23187 and radioimmunoassay of LTB, and TxB ? . This test provides an indication of the bioavailability of a test compound as an inhibitor of 5-L0 or cyclooxygenase. c) An _irι vivo system involving measuring the effects of a test compound administered orally to a group of male rats against the liberation of LTB, induced by zymosan within an air pouch generated within the subcutaneous tissue of the back of the rats. The rats are anaesthetised and air pouches are formed by the injection of sterile air (20ml). A further injection of air (10ml) is similarly given after 3 days. At 6 days after the initial air injection the test compound is administered (usually orally as the suspension produced when a solution of the test compound in dimethylsulphoxide is added to hydroxypropylmethylcellulose), followed by the intrapouch injection of zymosan (1ml of a 1% suspension in physiological saline). After 3 hours the rats are killed, the air pouches are lavaged with physiological saline, and the specific radioimmunoassay described above is used to assay LTB, in the washings. This test provides an indication of inhibitory effects against 5-L0 in an inflammatory milieu. Although the pharmacological properties of the compounds of the formula I vary with structural changes as expected, in general compounds of the formula I possess 5-L0 inhibitory effects at the following concentrations or doses in at least one of the above tests a)-c):- Test a): IC 50 (LTB 4 ) in the range, for example, 0.01-40μM IC c0 (TxB 2 ) in the range, for example, 40-200μM; Test b) : oral ED,- 0 (LTB,) in the range, for example, 0.1-lOOmg/kg; Test c): oral ED (LTB,) in the range, for example, 0.1-lOOmg/kg. No overt toxicity or other untoward effects are present in tests b) and/or c) when compounds of the formula I are administered at several multiples of their minimum inhibitory dose or concentration. Thus, by way of example, the compound (2S,4R)-4-[5-fluoro-3- (l-methyl-2-oxo-l,2,3,4-tetrahydroquinolin-6-ylsulphonyl)phenyl]-4- methoxy-2-methyltetrahydropyran has an IC of 0.07μM against LTB, in test a), and an ED,- 0 of approximately 0.25 mg/kg against LTB, in test c). These compounds are examples of compounds of the invention which show selective inhibitory properties for 5-L0 as opposed to cyclooxygenase, which selective properties are expected to impart improved therapeutic properties, for example, a reduction in or freedom from the gastrointestinal side-effects frequently associated with cyclooxygenase inhibitors such as indomethacin. According to a further feature of the invention there is provided a pharmaceutical composition which comprises a 2-oxo-l,2,3,4- tetrahydroquinoline derivative of the formula I, or a pharmaceutically-acceptable salt thereof, in association with a pharmaceutically-acceptable diluent or carrier. The composition may be in a form suitable for oral use, for example a tablet, capsule, aqueous or oily solution, suspension or emulsion; for topical use, for example a cream, ointment, gel or aqueous or oily solution or suspension; for nasal use, for example a snuff, nasal spray or nasal drops; for vaginal or rectal use, for example a suppository; for administration by inhalation, for example as a finely divided powder such as a dry powder, a microcrystalline form or a liquid aerosol; for sub-lingual or buccal use, for example a tablet or capsule; or for parenteral use (including intravenous, subcutaneous, intramuscular, intravascular or infusion), for example a sterile aqueous or oily solution or suspension. In general the above compositions may be prepared in a conventional manner using conventional excipients. The amount of active ingredient (that is a 2-oxo-l,2,3,4- tetrahydroquinoline derivative of the formula I, or a pharmaceutically-acceptable salt thereof) that is combined with one or more excipients to produce a single dosage form will necessarily vary depending upon the host treated and the particular route of administration. For example, a formulation intended for oral administration to humans will generally contain, for example, from 0.5 mg to 2 g of active agent compounded with an appropriate and convenient amount of excipients which may vary from about 5 to about 98 percent by weight of the total composition. Dosage unit forms will generally contain about 1 mg to about 500 mg of an active ingredient. According to a further feature of the invention there is provided a 2-oxo-l,2,3,4-tetrahydroquinoline derivative of the formula I, or a pharmaceutically-acceptable salt thereof, for use in a method of treatment of the human or animal body by therapy. The invention also includes a method of treating a disease or medical condition mediated alone or in part by one or more leukotrienes which comprises administering to a warm-blooded animal requiring such treatment an effective amount of an active ingredient as defined above. The invention also provides the use of such an active ingredient in the production of a new medicament for use in a leukotriene mediated disease or medical condition. The size of the dose for therapeutic or prophylactic purposes of a compound of the formula I will naturally vary according to the nature and severity of the conditions, the age and sex of the animal or patient and the route of administration, according to well known principles of medicine. As mentioned above, compounds of the formula I are useful in treating those diseases such as allergic and inflammatory conditions and disorders of bone metabolism which are due alone or in part to the effects of the metabolites of arachidonic acid arising by the linear (5-L0 catalysed) pathway and in particular the leukotrienes, the production of which is mediated by 5-L0. As previously mentioned, such conditions include, for example, asthmatic conditions, allergic reactions, allergic rhinitis, allergic shock, psoriasis, atopic dermatitis, cardiovascular and cerebrovascular disorders, arthritic and inflammatory joint disease, inflammatory bowel diseases, conjunctivitis, the conditions of shock or trauma and various disorders of bone metabolism. In using a compound of the formula I for therapeutic or prophylactic purposes it will generally be administered so that a daily dose in the range, for example, 0.5 mg to 75 mg per kg body weight is received, given if required in divided doses. In general lower doses will be administered when a parenteral route is employed. Thus, for example, for intravenous administration, a dose in the range, for example, 0.5 mg to 30 mg per kg body weight will generally be used. Similarly, for administration by inhalation, a dose in the range, for example, 0.5 mg to 25 mg per kg body weight will be used. Although the compounds of the formula I are primarily of value as therapeutic agents for use in warm-blooded animals (including man) , they are also useful whenever it is required to inhibit the enzyme 5-L0. Thus, they are useful as pharmacological standards for use in the development of new biological tests and in the search for new pharmacological agents. By virtue of their effects on leukotriene production, the compounds of the formula I have certain cytoprotective effects, for example they are useful in reducing or suppressing certain of the adverse gastrointestinal effects of the cyclooxygenase inhibitory non- steroidal anti-inflammatory agents (NSAIA), such as indomethacin, acetylsalicylic acid, ibuprofen, sulindac, tolmetin and piroxicam. Furthermore, co-administration of a 5-L0 inhibitor of the formula I with a NSAIA can result in a reduction in the quantity of the latter agent needed to produce a therapeutic effect, thereby reducing the likelihood of adverse side-effects. According to a further feature of the invention there is provided a pharmaceutical composition which comprises a 2-oxo-l,2,3,4-tetrahydroquinoline derivative of the formula I, or a pharmaceutically-acceptable salt thereof as defined hereinbefore, in conjunction or admixture with a cyclooxygenase inhibitory non-steroidal anti-inflammatory agent (such as those mentioned above), and a pharmaceutically-acceptable diluent or carrier. The cytoprotective effects of the compounds of the formula I may be demonstrated, for example in a standard laboratory model which assesses protection against indomethacin-induced or ethanol-induced ulceration in the gastrointestinal tract of rats. The compositions of the invention may in addition contain one or more therapeutic or prophylactic agents known to be of value for the disease under treatment. Thus, for example a known platelet aggregation inhibitor, hypolipidemic agent, anti-hypertensive agent, beta-adrenergic blocker or a vasodilator may usefully also be present in a pharmaceutical composition of the invention for use in treating a heart or vascular disease or condition. Similarly, by way of example, an anti-histamine, steroid (such as beclomethasone dipropionate), sodium cromoglycate, phosphodiesterase inhibitor or a beta-adrenergic stimulant may usefully also be present in a pharmaceutical composition of the invention for use in treating a pulmonary disease or condition. The invention will now be illustrated in the following non-limiting Examples in which, unless otherwise stated:- (i) evaporations were carried out by rotary evaporation in vacuo and work-up procedures were carried out after removal of residual solids by filtration; (ii) operations were carried out at room temperature, that is in the range 18-25°C and under an atmosphere of an inert gas such as argon; (iii) column chromatography (by the flash procedure) and medium pressure liquid chromatography (MPLC) were performed on Merck Kieselgel silica (Art. 9385) or Merck Lichroprep RP-18 (Art. 9303) reversed-phase silica obtained from E. Merck, Darmstadt, Germany; (iv) yields are given for illustration only and are not necessarily the maximum attainable; (v) the end-products of the formula I have satisfactory microanalyses and their structures were confirmed by nuclear magnetic resonance (NMR) and mass spectral techniques; unless otherwise stated, CDCl solutions of the end-products of the formula I were used for the determination of NMR spectral data, chemical shift values were measured on the delta scale; the following abbreviations have been used: s, singlet; d, doublet; t, triplet; q, quartet; m, multiplet; (vi) intermediates were not generally fully characterised and purity was assessed by thin layer chromatographic, infra-red (IR) or NMR analysis; (vii) melting points are uncorrected and were determined using a Mettler SP62 automatic melting point apparatus or an oil-bath apparatus; melting points for the end-products of the formula I were determined after crystallisation from a conventional organic solvent such as ethanol, methanol, acetone, ether or hiexane, alone or in admixture; and (viii) the following abbreviation has been used:- NMP N-methylpyrrolidin-2-one; DMF N,N-dimethylformamide; THF tetrahydrofuran. Example 1 n-Butyl-lithium (1.4M in hexane, 1.5 ml) was added dropwise to a stirred mixture of 6-mercapto-l-methyl-l,2,3,4-tetrahydro- quinolin-2-one (0.386 g), 4-(3,5-difluorophenyl)-4-methoxytetrahydro- pyran (European Patent Application No. 0462813, Example 5 thereof; 0.547 g) and NMP (6 ml) which had been cooled to 0°C. The mixture was stirred at 0°C for 5 minutes and then heated to 145°C for 2.2 hours with the concomitant distillation of the hexane. The mixture was cooled to ambient temperature and partitioned between ethyl acetate and water. The organic phase was washed with water, with a 0.5N sodium hydroxide solution and with brine, dried (MgSO.) and evaporated. The residue was purified by column chromatography using increasingly polar mixtures of methylene chloride and diethyl ether as eluent. The oil so obtained was triturated under diethyl ether. There was thus obtained 4-[5-fluoro-3-(l-methyl-2-oxo-l,2,3,4-tetra- hydroquinolin-6-ylthio)phenyl]-4-methoxytetrahydropyran (0.404 g, 50%), m.p. 124-125°C; NMR Spectrum 1.8-2.1 (m, 4H), 2.55-3.0 (m, 4H), 2.99 (s, 3H), 3.38 (s, 3H), 3.7-4.0 (m, 4H) , 6.7-7.15 (m, 4H) , 7.2-7.5 (m, 2H). The 6-mercapto-1-methyl-1,2,3,4-tetrahydroquinolin-2-one used as a starting material was obtained as follows:- A mixture of concentrated hydrochloric acid (5 drops) and water (50 ml) was added to a stirred mixture of di-(l-methyl-2-oxo- l,2,3,4-tetrahydroquinolin-6-yl) disulphide (European Patent Application No. 0462812, Example 7 thereof; 38.4 g), triphenylphosphine (29 g) and 1,4-dioxan (300 ml). The mixture was stirred at ambient temperature for 30 minutes. The mixture was concentrated by evaporation to reduce the volume by approximately one half. The residue was partitioned between ethyl acetate and 0.5N aqueous sodium hydroxide solution. The aqueous phase was washed with diethyl ether and then acidified to pH2 by the addition of dilute aqueous hydrochloric acid. The acidic mixture was extracted with ethyl acetate. The organic phase was dried (MgSO.) and evaporated. The residual oil was dissolved in diethyl ether and hexane was added. There was thus obtained 6-mercapto-l-methyl-l,2,3,4-tetrahydro- quinolin-2-one as a solid (35.5 g, 92%) which was used without further purification. Example 2 A mixture of 6-mercapto-l-methyl-l,2,3,4-tetrahydroquinolin- 2-one (0.247 g) , (2S,4R)-4-(3,5-difluorophenyl)-4-methoxy-2-methyl- tetrahydropyran (European Patent Application No. 0462813, Example 10 thereof; 0.31 g) , lithium hydroxide monohydrate (0.056 g), di-(2-methoxyethyl) ether (1 ml) and NMP (4 ml) was stirred and heated to 140°C for 2 hours. The mixture was cooled to ambient temperature and partitioned between ethyl acetate and water. The organic phase was washed with water, with IN aqueous hydrochloric acid and with brine, dried (MgSO,) and evaporated. The residue was purified by column chromatography using increasingly polar mixtures of methylene chloride and diethyl ether as eluent. The oil so obtained was triturated under diethyl ether. There was thus obtained (2S,4R)-4-[5- fluoro-3-(l-methyl-2-oxo-1,2,3,4-tetrahydroquinolin-6-ylthio)phenyl]- 4-methoxy-2-methyltetrahydropyran (0.135 g, 25%), m.p. 137-139°C; NMR Spectrum 1.18 (d, 3H), 1.4-2.2 (m, 4H) , 2.50-2.96 (m, 4H) , 2.98 (s, 3H), 3.37 (s, 3H), 3.65-4.15 (m, 3H), 6.65-7.50 (m, 6H) . Example 3 A mixture of 6-iodo-l-methyl-l,2,3,4-tetrahydroquinolin-2- one (0.29 g), (2S,4R)-4-(3-mercaptophenyl)-4-methoxy-2-methyltetra- hydropyran (European Patent Application No. 0420511, Example 6 thereof; 0.26 g), cuprous chloride (0.02 g), potassium carbonate (0.15 g) and DMF (3 ml) was stirred and heated to 120°C for 75 minutes. The mixture was cooled to ambient temperature and partitioned between methylene chloride and water. The organic phase was washed with water, dried (MgSO.) and evaporated. The residue was purified by column chromatography using increasingly polar mixtures of hexane and ethyl acetate as eluent. There was thus obtained (2S,4R)-4-methoxy-4-[3-(l-methyl-2-oxo-1,2,3,4-tetrahydroquinolin-6- ylthio)phenyl]-2-methyltetrahydropyran (0.25 g, 63%), m.p. 112-115°C; NMR Spectrum 1.2 (d, 3H) , 1.55 (m, 1H), 1.9 (m, 3H), 2.65 (m, 2H), 2.85 (m, 2H), 3.2 (s, 3H) , 3.4 (s, 3H), 3.9 (m, 3H), 6.95 (d, 1H) , 7.1-7.4 (m, 6H). The 6-iodo-l-methyl-l,2,3,4-tetrahydroquinolin-2-one used as a starting material was obtained as follows:- A mixture of l-methyl-2-oxo-l,2-dihydroquinolin-2-one (European Patent Application No. 0420511, Example 1 thereof; 8 g) , 10% palladium-on-charcoal catalyst (2 g) and ethanol (60 ml) was stirred under a pressure of 3.5 atmospheres of hydrogen for 24 hours. The mixture was filtered and evaporated. The residue was purified by column chromatography using a 9:1 mixture of methylene chloride and diethyl ether as eluent. There was thus obtained l-methyl-2-oxo-l,2,3,4-tetrahydroquinolin-2-one (7.88 g, 98%) as an oil. A mixture of a portion (1.2 g) of the product so obtained, iodine monochloride (1.9 g) and glacial acetic acid (25 ml) was stirred and heated to 80°C for 2 hours. The mixture was cooled to ambient temperature and poured into a dilute aqueous sodium thiosulphate solution. The mixture was neutralised by the addition of sodium bicarbonate and extracted with ethyl acetate. The organic phase was washed with water, with a saturated aqueous sodium bicarbonate solution and with brine, dried (MgSO, ) and evaporated. The residue was recrystallised from a mixture of hexane and ethyl acetate. There was thus obtained 6-iodo-l-methyl-l,2,3,4-tetrahydro- quinolin-2-one (1.09 g, 51%); NMR Spectrum (CD 3 S0CD 3 ) 2.65 (t, 2H), 2.85 (t, 2H), 3.2 (s, 3H) , 6.9 (d, 1H), 7.6 (m, 2H) . Example 4 Potassium peroxymonosulphate (4.4 g) was added to a mixture of (2S,4R)-4-[5-fluoro-3-(l-methyl-2-oxo-1,2,3,4-tetrahydroquinolin-6- ylthio)phenyl]-4-methoxy-2-methyltetrahydropyran (2 g), ethanol (20 ml) and water (10 ml). The mixture was stirred at ambient temperature for 18 hours. The mixture was partitioned between methylene chloride and water. The organic phase was washed with an aqueous sodium bisulphite solution, dried (MgSO.) and evaporated. The residue was purified by column chromatography using increasingly polar mixtures of hexane and ethyl acetate as eluent. The solid so obtained was recrystallised from a mixture of hexane and ethyl acetate. There was thus obtained (2S, R)-4-[5-fluoro-3-(l-methyl-2-oxo-1,2,3,4-tetra- hydroquinolin-6-ylsulphonyl)phenyl]-4-methoxy-2-methyltetrahydropyran (1.3 g, 60%), m.p. 110-112°C; NMR Spectrum 1.2 (d, 3H) , 1.55 (m, IH), 1.9 (m, 2H) , 2.7 (m, 2H), 3.0 (m, 5H), 3.4 (s, 3H) , 3.9 (m, 3H), 7.1 (d, IH), 7.3 (m, IH) , 7.5 (m, IH), 7.75 (m, 2H) , 7.85 (q, IH). Example 5 Using an analogous procedure to that described in Example 4, (2S,4R)-4-methoxy-4-[3-(l-methyl-2-oxo-l,2,3,4-tetrahydroquinolin-6- ylthio)phenyl]-2-methyltetrahydropyran was oxidised to give (2S,4R)-4- methoxy-4-[3-(l-methyl-2-oxo-l,2,3,4-tetrahydroquinolin-6- ylsulphonyl)phenyl]-2-methyltetrahydropyran in 57% yield, m.p. 144-147°C; NMR Spectrum 1.22 (d, 3H), 1.6 (m, IH), 2.0 (m, 3H), 2.7 (t, 2H) , 3.0 (t, 2H), 3.0 (s, 3H), 3.4 (s, 3H) , 3.9 (m, 3H) , 7.05 (d, IH) , 7.6 (m, 2H), 7.7 (m, IH), 7.85 (m, 2H) , 8.0 (s, IH). Example 6 Using an analogous procedure to that described in Example 4, 4-[5-fluoro-3-(l-methyl-2-oxo-1,2,3,4-tetrahydroquinolin-6-ylthio)- phenyl]-4-methoxytetrahydropyran was oxidised to give 4-[5-fluoro-3- (l-methyl-2-oxo-1,2,3,4-tetrahydroquinolin-6-ylsulphonyl)phenyl]-4- methoxytetrahydropyran in 80% yield, m.p. 140-142°C; NMR Spectrum 2.0 (m, 4H) , 2.7 (m, 2H), 3.0 (m, 5H) , 3.35 (s, 3H) , 3.8 (m, 4H), 7.1 (d, IH) , 7.55 (m, IH) , 7.75 (m, 2H) , 7.85 (m, IH). Example 7 A mixture of 6-mercapto-l-methyl-1,2,3, -tetrahydroquinolin- 2-one (0.38 g), 4-methoxy-4-(2,3,5-trifluorophenyl)tetrahydropyran (0.5 g), lithium hydroxide monohydrate (0.085 g) and NMP (5 ml) was stirred and heated to 90°C for 2 hours. The mixture was cooled to ambient temperature and partitioned between diethyl ether and water. The organic phase was washed with brine, dried (MgSO.) and evaporated. The residue was triturated under a mixture of ethyl acetate and hexane. There was thus obtained 4-[2,5-difluoro-3-(l-methyl-2-oxo- 1,2,3,4-tetrahydroquinolin-6-ylthio)phenyl]-4-methoxytetrahydropyran (0.31 g, 37%), m.p. 142-144°C; NMR Spectrum 2.1 (m, 4H), 2.7 (t, 2H), 2.9 (t, 2H) , 3.1 (s, 3H) , 3.4 (s, 3H), 3.8 (m, 4H), 6.5 (m, IH) , 6.8 ( , IH) , 7.0 (d, IH), 7.3 (d, IH), 7.4 (q, IH). The 4-methoxy-4-(2,3,5-trifluorophenyl)tetrahydropyran used as a starting material was obtained as follows:- l-Bromo-2,3,5-trifluorobenzene (0.15 ml) and 1,2-dibromoethane (0.03 ml) were added in turn to a stirred mixture of magnesium (0.075 g) and THF (3 ml). The mixture was warmed to initiate the formation of a Grignard reagent. A second portion (0.15 ml) of l-bromo-2,3,5-trifluorobenzene was added and the mixture was stirred at ambient temperature for 30 minutes. A solution of tetrahydropyran-4-one (0.2 ml) in THF (1 ml) was added and the mixture was stirred at ambient temperature for 30 minutes. The mixture was partitioned between diethyl ether and a saturated aqueous ammonium chloride solution. The organic solution was washed with water and with brine, dried (MgSO.) and evaporated. The residue was purified by column chromatography using increasingly polar mixtures of hexane and ethyl acetate as eluent. There was thus obtained 4-hydroxy-4-(2,3,5- trifluorophenyl)tetrahydropyran (0.25 g) as a gum; NMR Spectrum 1.7 (m, 2H) , 2.1 (d, IH) , 2.4 (m, 2H) , 3.9 (m, 4H), 6.9 (m, IH), 7.1 (m, IH) . After appropriate repetition of the above-mentioned step, sodium hydride (60% dispersion in mineral oil, 0.4 g) was added portionwise to a stirred mixture of 4-hydroxy-4-(2,3,5- trifluorophenyl)tetrahydropyran (1.8 g), methyl iodide (4.4 g) and NMP (15 ml). The mixture was stirred at ambient temperature for 1 hour. The mixture was evaporated and the residue was partitioned between diethyl ether and water. The organic phase was washed with brine, dried (MgSO,) and evaporated. There was thus obtained 4-methoxy-4- (2,3,5-trifluorophenyl)tetrahydropyran in quantitative yield which was used without further purification. Example 8 Using an analogous procedure to that described in Example 7, 6-mercapto-l-methyl-l,2,3,4-tetrahydroquinolin-2-one was reacted with (2S,4R)-4-methoxy-2-methyl-4-(2,3,5-trifluorophenyl)tetrahydropyran to give (2S,4R)-4-[2,5-difluoro-3-(l-methyl-2-oxo-1,2,3,4-tetrahydro- quinolin-6-ylthio)phenyl]-4-methoxy-2-methyltetrahydropyran in 15% yield, m.p. 119-121°C; NMR Spectrum 1.2 (d, 3H) , 1.7 (q, IH) , 2.1 (m, 3H), 2.7 (t, 2H), 2.9 (t, 2H), 3.1 (s, 3H), 3.4 (s, 3H) , 3.9 (m, 3H) , 6.5 (m, IH) , 6.9 (m, IH), 7.0 (d, IH), 7.3 (d, IH), 7.4 (q, IH) . The (2S,4R)-4-methoxy-2-methyl-4-(2,3,5-trifluorophenyl)- tetrahydropyran used as a starting material was obtained using analogous procedures to those described in the portion of Example 7 which is concerned with the preparation of starting materials except that (2S)-2-methyltetrahydropyran-4-one (European Patent Application No. 0385662, Example 20 thereof) was used in place of tetrahydropyran- 4-one. Example 9 Using an analogous procedure to that described in Example 4, (2S,4R)-4-[2,5-difluoro-3-(l-methyl-2-oxo-l,2,3,4-tetrahydroquinolin- 6-ylthio)phenyl]-4-methoxy-2-methyltetrahydropyran was oxidised to give (2S,4R)-4-[2,5-difluoro-3-(l-methyl-2-oxo-1,2,3,4-tetrahydro- quinolin-6-ylsulphonyl)phenyl]-4-methoxy-2-methyltetrahydropyran in 20% yield, m.p. 141-143°C; NMR Spectrum 1.2 (d, 3H) , 1.6-2.2 (m, 4H), 2.7 (q, 2H) , 3.0 (q, 2H) , 3.05 (s, 3H), 3.4 (s, 3H), 3.9 (m, 3H) , 7.1 (d, IH) , 7.35 (m, IH), 7.8 (m, 2H), 7.9 (m, IH). Example 10 Using an analogous procedure to that described in Example 7, 6-mercapto-l-methyl-l,2,3,4-tetrahydroquinolin-2-one was reacted with 4-(3,4-difluorophenyl)-4-methoxytetrahydropyran to give a mixture of two products. The mixture was separated by column chromatography using increasingly polar mixtures of hexane and ethyl acetate as eluent. There were thus obtained:- 4-[4-fluoro-3-(l-methyl-2-oxo-1,2,3,4-tetrahydroquinolin-6-ylthio)- phenyl]-4-methoxytetrahydropyran in 16% yield; NMR Spectrum 2.0 (m, 4H), 2.65 (q, 2H), 2.9 (q, 2H), 2.95 (s, 3H), 3.35 (s, 3H), 3.8 (m, 4H) , 6.9 (d, IH) , 7.1 (t, IH) , 7.3 (m, 3H) ; and 4-[3-fluoro-4-(l-methyl-2-oxo-l,2,3,4-tetrahydroquinolin-6- ylthio)phenyl]-4-methoxytetrahydropyran in 13% yield; NMR Spectrum 2.0 (m, 4H) , 2.7 (q, 2H) , 2.9 (q, 2H), 3.0 (s, 3H), 3.35 (s, 3H), 3.8 (m, 4H), 6.95 (d, IH) , 7.1 (m, 3H) , 7.25 (s, IH), 7.35 (q, IH). The 4-(3,4-difluorophenyl)-4-methoxytetrahydropyran used as a starting material was obtained using analogous procedures to those described in the portion of Example 7 which is concerned with the preparation of starting materials except that l-bromo-3,4-difluoro- benzene was used in place of l-bromo-2,3,5-trifluorobenzene. TS37620 09MAY94 BST/MB

Claims: CLAIMS 1. A 2-oxo-l,2,3,4-tetrahydroquinoline derivative of the formula I OR 1 I Q-X 1 -Ar-C-R 2 I I R 3 wherein Q is 2-oxo-l,2,3,4-tetrahydroquinolin-6-yl which bears on the nitrogen atom at the 1-position a (l-4C)alkyl substituent; X is thio, sulphinyl or sulphonyl; Ar is 1,3-phenylene which may optionally bear one or two halogeno substituents; R 1 is (l-4C)alkyl, (3-4C)alkenyl or (3-4C)alkynyl; and 2 3 2 2 3 R and R together form a group of the formula -A -X -A - which 2 3 together with the carbon atom to which A and A are attached define a 2 3 ring having 5 or 6 ring atoms, wherein A and A , which may be the same 2 or different, each is (l-3C)alkylene and X is oxy, and which ring may bear one or two (1-4C)alkyl substituents; or a pharmaceutically-acceptable salt thereof. 2. A 2-oxo-l,2,3,4-tetrahydroquinoline derivative of the formula I as claimed in claim 1 wherein Q is l-methyl-2-oxo-l,2,3,4- tetrahydroquinolin-6-yl; X is thio or sulphonyl; Ar is 1,3-phenylene or 5-fluoro-l,3-phenylene; R is methyl; and 2 3 2 2 3 R and R together form a group of the formula -A -X -A - which 2 3 together with the carbon atom to which A and A are attached define a 2 3 2 ring having 6 ring atoms, wherein each of A and A is ethylene and X 2 is oxy, and which ring may bear a methyl substituent alpha to X ; or a pharmaceutically-acceptable salt thereof. 3. A 2-oxo-l,2,3,4-tetrahydroquinoline derivative of the formula I as claimed in claim 1 wherein Q is l-methyl-2-oxo-l,2,3,4- tetrahydroquinolin-6-yl; X is thio or sulphonyl; Ar is 1,3-phenylene, 5-fluoro-l,3-phenylene or 2,5-difluoro-1,3-phenylene; R is methyl; and 2 3 2 2 3 R and R together form a group of the formula -A -X -A - which 2 3 together with the carbon atom to which A and A are attached define a 2 3 2 ring having 6 ring atoms, wherein each of A and A is ethylene and X 2 is oxy, and which ring may bear a methyl substituent alpha to X ; or a pharmaceutically-acceptable salt thereof. 4. A 2-oxo-l,2,3, -tetrahydroquinoline derivative of the formula I as claimed in claim 1 wherein Q is l-methyl-2-oxo-l,2,3,4- tetrahydroquinolin-6-yl; X is thio or sulphonyl; Ar is 5-fluoro-1,3-phenylene; R is methyl; and 2 3 R and R together form a group of the formula -CH 2 CH 2 0CH(CH.)CH 2 -; or a pharmaceutically-acceptable salt thereof. 5. A 2-oxo-l,2,3,4-tetrahydroquinoline derivative of the formula I as claimed in claim 1 wherein Q is l-methyl-2-oxo-l,2,3,4- tetrahydroquinolin-6-yl; X is thio or sulphonyl; Ar is 5-fluoro-l,3-phenylene or 2,5-difluoro-1,3-phenylene; R is methyl; and 2 3 R and R together form a group of the formula -CH 2 CH 2 0CH(CH 3 )CH 2 -; or a pharmaceutically-acceptable salt thereof. 6. A 2-oxo-l,2,3,4-tetrahydroquinoline derivative of the formula I as claimed in claim 1 selected from:- (2S,4R)-4-[5-fluoro-3-(l-methyl-2-oxo-1,2,3, -tetrahydroquinolin-6- ylthio)phenyl]-4-methoxy-2-methyltetrahydropyran, (2S,4R)-4-[5-fluoro-3-(l-methyl-2-oxo-l,2,3,4-tetrahydroquinolin-6- ylsulphonyl)phenyl]-4-methoxy-2-methyltetrahydropyran and (2S,4R)-4-[2,5-difluoro-3-(l-methyl-2-oxo-l,2,3,4-tetrahydroquinolin- 6-ylthio)phenyl]-4-methoxy-2-methyltetrahydropyran. 7. A process for the preparation of a 2-oxo-l,2,3,4- tetrahydroquinoline derivative of the formula I, or a pharmaceutically-acceptable salt thereof, as claimed in anyone of claims 1 to 6 which comprises:- (a) the coupling of a compound of the formula Q-X -H with a compound of the formula II OR Z-Ar-C-R II R- wherein Z is a displaceable group; (b) the coupling of a compound of the formula Q-Z, wherein Z is a displaceable group, with a compound of the formula III OR 1 I H-X 1 -Ar-C-R 2 III I R 3 (c) the coupling of a compound of the formula Q-X -Z, wherein Z is a displaceable group or, when X is a thio group, Z may be a group of the formula Q-X -, with an organometallic reagent of the formula IV OR 1 I M-Ar-C-R 2 IV I R 3 wherein M is an alkali metal or alkaline earth metal or M represents the magnesium halide portion of a conventional Grignard reagent; (d) the alkylation a compound of the formula V OH I Q-X 1 -Ar-C-R 2 V I R 3 with a compound of the formula R -Z, wherein Z is a displaceable group; (e) for the production of those compounds of the formula I wherein Q bears an alkyl substituent on an available nitrogen atom, the alkylation of a compound of the formula I wherein Q bears a hydrogen atom on said available nitrogen atom; or (f) for the production of those compounds of the formula I wherein X is a sulphinyl or sulphonyl group, the oxidation of a compound of the formula I wherein X is a thio group; and when a pharmaceutically-acceptable salt of a novel compound of the formula I is required, it may be obtained by reaction of said compound with a suitable acid or base using a conventional procedure, and when an optically active form of a compound of the formula I is required, it may be obtained by carrying out one of the aforesaid procedures using an optically active starting material, or by resolution of a racemic form of said compound using a conventional procedure. 8. A pharmaceutical composition which comprises a 2-oxo-l,2,3,4- tetrahydroquinoline derivative of the formula I, or a pharmaceutically-acceptable salt thereof, as claimed in any one of claims 1 to 6 in association with a pharmaceutically-acceptable diluent or carrier. 9. The use of a 2-oxo-l,2,3,4-tetrahydroquinoline derivative of the formula I, or a pharmaceutically-acceptable salt thereof, as claimed in any one of claims 1 to 6 in the production of a new medicament for use in a leukotriene mediated disease or medical condition.

Inventors: BRUNEAU PIERRE ANDRE RAYMOND, EDWARDS PHILIP NEIL, BRUNEAU, PIERRE, ANDRE, RAYMOND, EDWARDS, PHILIP, NEIL
Applicants: BRUNEAU PIERRE ANDRE RAYMOND, EDWARDS PHILIP NEIL, ZENECA LTD, ZENECA PHARMA SA, BRUNEAU, PIERRE, ANDRE, RAYMOND, EDWARDS, PHILIP, NEIL, ZENECA LIMITED, ZENECA-PHARMA S.A.
Application year: 1994
Main classification: C07D405
IPC codes: A61K31, A61P11, A61P27, A61P37, A61P43, C07D405